Inhibition of myelin regeneration by tenascin proteins and the associated matrisom

• Applicant: Professor Dr. Andreas Faissner
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Developmental Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407698736

The ordered axonal connections generate neuronal networks that are organized in neuroanatomical systems. Integrity of these networks and undisturbed information transfer at synapses are prerequisites for the correct functioning of the central nervous system (CNS). Beyond the architecture of connectivity, adequate functioning also requires rapid information transfer by axonal connections. In the mammalian CNS, most of the large axons are enwrapped by myelin sheaths that are produced by specialized cells, the mature oligodendrocytes. The myelin sheath underlies the saltatory conduction of action potentials and secures fast information transmission. Furthermore, it provides metabolic support and contributes to the maintenance of axonal integrity. During the process of myelination, myelin membranes wrap around axons in a spiral manner, resulting in a multilamellar compacted myelin sheath. Oligodendrocytes represent an independent glial lineage of the CNS. They arise from radial glia cells, the principal neural stem and glial progenitor cell (NSPC) compartment during neural development. Gliogenesis begins with the specification of oligodendrocyte precursor cells (OPCs) that are born in distinct regions of the developing neural tube. In the caudal region, they emerge in the ventral neural tube under the influence of morphogens, close to the midline. For a long time period, myelin has been considered a rather inert structure, but meanwhile it is clear that the myelin sheath is continuously reorganized in the human in the context of postnatal development, various physiological processes and aging. Furthermore, the ability of reorganizing the myelin sheath also reflects that myelin is an essentially regenerating system. This is of interest in the context of lesion because various disease conditions of the CNS involve a destruction of the myelin sheaths, with resulting functional impairments. It is known that mature oligodendrocytes do not regenerate myelin defects. Hence, the oligodendrocyte precursor cells (OPCs) that populate the CNS have the task to repair myelin deficits. However, extrinsic factors hinder the regeneration process in the adult CNS. The laboratory has characterized constituents of the extracellular matrix (ECM) of the CNS, which is part of a complex molecular system known as the matrisome. In their preliminary work the laboratory has shown that distinct tenascin proteins and the associated interactome of the neural matrisome are upregulated in CNS lesions and interfere in distinct ways with the differentiation of OPCs. In the present proposal, we suggest to study cellular and molecular bases of the matrisome-dependent inhibition of remyelination. The aim is to understand the matrisome-based inhibitors of myelin regeneration in order to find ways to promote the reformation of myelin and the restitution of function in myelin associated disease processes.

• DFG Programme: Research Grants